Sublingual apomorphine

ABSTRACT

The invention features sublingual formulations of apomorphine and apomorphine prodrugs, and methods of treating Parkinson&#39;s disease, sexual dysfunction, and depressive disorders therewith.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. Provisional Application No.61/186,445, filed on Jun. 12, 2009, which is incorporated by referenceherein in its entirety.

BACKGROUND OF THE INVENTION

The invention relates to compositions including apomorphine, or anapomorphine prodrug, and formulated for sublingual administration andthe use of such compositions for the treatment of Parkinson's disease.

Parkinson's disease (PD) is a progressive degenerative disease of thecentral nervous system. The risk of developing Parkinson's diseaseincreases with age, and afflicted individuals are usually adults over40. Parkinson's disease occurs in all parts of the world, and affectsmore than 1.5 million individuals in the United States alone.

While the primary cause of Parkinson's disease is not known, it ischaracterized by degeneration of dopaminergic neurons of the substantianigra. The substantia nigra is a portion of the lower brain, or brainstem that helps control voluntary movements. The shortage of dopamine inthe brain caused by the loss of these neurons is believed to cause theobservable disease symptoms.

The symptoms of PD vary from patient to patient. The most common symptomis a paucity of movement and rigidity, characterized by an increasedstiffness of voluntary skeletal muscles. Additional symptoms includeresting tremor, bradykinesia (slowness of movement), poor balance, andwalking problems. Common secondary symptoms include depression, sleepdisturbance, dizziness, stooped posture, dementia, problems with speech,breathing, and swallowing. The symptoms become progressively worse withtime and ultimately result in death.

A variety of therapeutic treatments for PD are available. Perhaps thebest known is levodopa, a dopamine precursor. While levodopaadministration can result in a dramatic improvement in symptoms,patients can experience serious side-effects, including nausea andvomiting. Concurrent carbidopa administration with levodopa is asignificant improvement, with the addition of carbidopa inhibitinglevodopa metabolism in the gut, liver and other tissues, therebyallowing more levodopa to reach the brain. Other dopamine agonists, suchas bromocriptine, pergolide, pramipexole, and andropinirole are alsoused to treat Parkinson's disease, and can be administered to PDpatients either alone or in combination with levodopa.

Many patients develop involuntary choreiform movements which are theresult of excessive activation of dopamine receptors. These movementsusually affect the face and limbs and can become very severe. Suchmovements disappear if the dose of dopamine precursor (e.g., levodopa)or dopamine agonist is reduced, but this typically causes rigidity toreturn. Moreover, the margin between the beneficial and the unwantedeffects appear to become progressively narrower as the period ofchemotherapeutic treatment lengthens.

A further complication of long-term chemotherapeutic treatment withdopamine agonists is the development of rapid fluctuations in clinicalstate where the patient switches suddenly between mobility andimmobility for periods ranging from a few minutes to a few hours. Thefluctuations are of several general types. “Wearing-off” phenomena aredeteriorations in the relief afforded by a dose of levodopa before thenext dose takes effect (Van Laar T., CNS Drugs, 17:475 (2003)). Becausethey are related to a patient's dose schedule, such periods are oftenrelatively predictable (Dewey R B Jr., Neurology, 62(suppl 4):S3-S7(2004)). In contrast, “on-off” phenomena are sudden transitions from an“on” period of levodopa benefit to an “off” period of akinesia,rigidity, and tremor that occur in minutes or even seconds, (Swope D M.,Neurology, 62(suppl 4):S27-S31 (2004)) with no discernible relation to apatient's dose schedule. Two other phenomena are the delayed “on”effect, in which levodopa's effects are substantially delayed, and dosefailure (also known as the no-“on” or skipped-dose effect), in which noeffects occur at all. These various “off” states can produce such anabrupt loss of mobility that the patient may suddenly stop while walkingor be unable to rise from a chair in which he had sat down normally afew moments earlier.

Subcutaneous injections of apomorphine have proved to be effective inthe treatment of “on-off” fluctuations in Parkinson's disease within 5to 15 minutes, and last for 45 to 90 minutes. Trials have shownconsistent reversal of “off” period akinesia, a decrease in dailylevodopa requirements and consequently a decrease in the amount of “on”period dyskinesias. Advantages over other dopamine agonists include aquick onset of action and lower incidence of psychologicalcomplications. For a “rescue therapy” in patients with “on-off”fluctuations, apomorphine also has the advantage over other dopamineagonists that it has a relatively short half-life.

Numerous formulations and routes of administration for apomorphine havebeen studied and apomorphine therapy has been found to be hampered byvarious complications. For example, oral administration of apomorphinetablets has required high doses to achieve the necessary therapeuticeffect because apomorphine administered by this route undergoesextensive metabolism in the small intestine and/or, upon absorption, inthe liver; sublingual administration of apomorphine tablets causedsevere stomatitis on prolonged use with buccal mucosal ulceration inhalf the patients treated (see Deffond et al., J. Neurol. Neurosurg.Psychiatry 56:101 (1993)); and intranasal administration producedtransient nasal blockage, burning sensation and swollen nose and lips(see Koller et al., Neurology 62:S22 (2004)). While subcutaneousinjections of apomorphine have proven effective, an injection by needleis difficult for Parkinson's patients because of impaired motorfunction. Furthermore, a common side effect of subcutaneous injection isthe development of nodules, which often become infected, necessitatingantiobiotic treatment or surgical debridement (see Prietz et al., J.Neurol. Neurosurg. Psychiatry 65:709 (1998)).

There is a need for new formulations of apomorphine and apomorphineprodrugs which are safe, effective, and easy for a Parkinson's patientto use.

SUMMARY OF THE INVENTION

The invention features sublingual formulations of apomorphine andapomorphine prodrugs. The formulations can be useful for the treatmentof Parkinson's disease, sexual dysfunction, and depressive disorderstherewith.

In a first aspect, the invention features a pharmaceutical compositionin unit dosage form (e.g., a lozenge, a pill, a tablet, a film, or astrip) formulated for sublingual administration, the unit dosage formhaving a first portion including an acid addition salt of apomorphine,or an apomorphine prodrug, and a second portion including a pHneutralizing agent (e.g., polyamines, calcium hydroxide, magnesiumhydroxide, potassium hydroxide, sodium hydroxide, calcium carbonate,iron carbonate, magnesium carbonate, zinc carbonate, sodium acetate,sodium carbonate, potassium carbonate, sodium bicarbonate, potassiumbicarbonate, sodium phosphate monobasic, sodium phosphate dibasic,sodium phosphate tribasic, potassium phosphate monobasic, potassiumphosphate dibasic, potassium phosphate tribasic, and mixtures thereof,or any other suitable base).

In certain embodiments, the unit dosage form is a film or a strip andwherein the unit dosage form includes a mucoadhesive polymer. Themucoadhesive polymer can be, without limitation, any mucoadhesivepolymer described herein.

In one particular embodiment, the acid addition salt of apomorphine, oran apomorphine prodrug, is apomorphine hydrochloride. In anotherparticular embodiment, the acid addition salt of apomorphine, or anapomorphine prodrug, is protonated apomorphine complexed to an anionicpolyelectrolyte or protonated apomorphine prodrug complexed to ananionic polyelectrolyte (e.g., alginates, carrageenan, xanthan gum,polyacrylate, or carboxymethylcellulose).

In still another embodiment, the pharmaceutical composition is a film ora strip, wherein the first portion is a first layer and the secondportion is a second layer, the first layer being acidic and includingthe acid addition salt of apomorphine, or an apomorphine prodrug, andthe second layer including the pH neutralizing agent.

In certain embodiments, the sublingual formulation includes anantioxidant. The antioxidant can be, without limitation, any antioxidantdescribed herein.

In particular embodiments, the sublingual formulation includes a firstportion that is a film including a solid solution of an acid additionsalt of apomorphine, or an apomorphine prodrug, and includes a secondportion that is a particulate base on or within the unit dosage form.The particulate base can include, for example, sodium carbonate,potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodiumphosphate monobasic, sodium phosphate dibasic, sodium phosphatetribasic, potassium phosphate monobasic, potassium phosphate dibasic,potassium phosphate tribasic, or a mixture thereof.

In still another embodiment, the first portion of the unit dosage formis separated from the second portion of the unit dosage form by abarrier (e.g., a film separating an acidic layer from a basic layer in amulti-layered film, or a coating on a particulate base or apomorphineparticle contained within the unit dosage form). The barrier can beneutral in pH (e.g., between 6 and 7.8), separating the acidic firstportion from the basic second portion of the unit dosage form.

In a related aspect, the invention features a pharmaceutical compositionformulated for sublingual administration including apomorphine particleshaving an effective particle size of from 20 nm to 10 μm, wherein theapomorphine particles include apomorphine, an apomorphine prodrug, or asalt thereof.

In certain embodiments, the pharmaceutical composition is in a unitdosage form selected from a lozenge, a pill, a tablet, a film, or astrip. In other embodiments, the pharmaceutical composition is asublingual gel.

The sublingual formulations can include apomorphine particles having aneffective particle size of from 1 μm to 10 μm (e.g., an effectiveparticle size of from 1 μm to 9 μm, from 1 μm to 8 μm, from 1 μm to 7μm, from 1 μm to 6 μm, from 1 μm to 5 μm, from 2 μm to 10 μm, from 3 μmto 10 μm, from 4 μm to 10 μm, from 2 μm to 7 μm, or from 2 μm to 6 μm).

In certain other embodiments, the sublingual formulations can includeapomorphine particles having an effective particle size of from 20 nm to1 μm (e.g., an effective particle size of from 20 nm to 1 μm, from 40 nmto 1 μm, from 60 nm to 1 μm, from 80 nm to 1 μm, from 100 nm to 1 μm,from 20 nm to 800 nm, from 20 nm to 700 nm, from 50 nm to 700 nm, from40 nm to 800 nm, from 60 nm to 800 nm, from 100 nm to 800 nm, from 60 nmto 700 nm, from 60 nm to 600 nm, from 100 nm to 600 nm, from 150 nm to800 nm, or from 150 nm to 600 nm).

In still other embodiments, the sublingual formulation includes amucoadhesive polymer. The mucoadhesive polymer can be, withoutlimitation, any mucoadhesive polymer described herein.

In certain embodiments, the sublingual formulation includes apomorphineparticle and the apomorphine particle include an acid addition salt ofapomorphine or an apomorphine prodrug. The acid addition salt can beapomorphine hydrochloride or any acid addition salt described herein.Alternatively, the acid addition salt can be the hydrochloride salt ofan apomorphine prodrug or any other acid addition salt described herein.

In a particular embodiment, the sublingual formulation in unit dosageform is a film or a strip including a mucoadhesive polymer. Themucoadhesive polymer can be, without limitation, any mucoadhesivepolymer described herein. For example, the film or strip can include afirst layer and a second layer, the first layer being acidic andincluding the apomorphine particles and the second layer including a pHneutralizing agent (e.g., polyamines, calcium hydroxide, magnesiumhydroxide, potassium hydroxide, sodium hydroxide, calcium carbonate,iron carbonate, magnesium carbonate, zinc carbonate, sodium acetate,sodium carbonate, potassium carbonate, sodium bicarbonate, potassiumbicarbonate, sodium phosphate monobasic, sodium phosphate dibasic,sodium phosphate tribasic, potassium phosphate monobasic, potassiumphosphate dibasic, potassium phosphate tribasic, and mixtures thereof,or any other suitable base).

In certain embodiments, the sublingual formulation includes anantioxidant. The antioxidant can be, without limitation, any antioxidantdescribed herein.

In another aspect, the invention features a pharmaceutical compositionformulated for sublingual administration including protonatedapomorphine, or an apomorphine prodrug, complexed to an anionicpolyelectrolyte (e.g., alginates, carrageenan, xanthan gum,polyacrylate, or carboxymethylcellulose). In certain embodiments, thesublingual formulation includes an antioxidant. The antioxidant can be,without limitation, any antioxidant described herein.

In particular embodiments, the pharmaceutical composition is in a unitdosage form selected from a lozenge, a pill, a tablet, a film, or astrip. In still other embodiments, the pharmaceutical composition is asublingual gel.

In another aspect, the invention features a pharmaceutical compositionin unit dosage form formulated for sublingual administration, the unitdosage form including from 2 to 50 mg of an apomorphine prodrug (e.g.,from 2 to 15 mg, 10 to 50 mg, 12 to 30 mg, 20 to 50 mg, 15 to 30 mg, or35 to 50 mg of an apomorphine prodrug). In particular embodiments, theunit dosage form is a lozenge, a pill, a tablet, a film, or stripincluding from the apomorphine prodrug in its free base form. In stillother embodiments, the unit dosage form is a lozenge, a pill, a tablet,a film, or strip including a solid solution of the apomorphine prodrugin its free base form.

In an embodiment of any of the above pharmaceutical compositions, thepharmaceutical composition is in a unit dosage form including from 2 to40 mg of apomorphine, an apomorphine prodrug, or an acid addition saltthereof (e.g., from 2 to 5 mg, 4 to 10 mg, 6 to 15 mg, 8 to 20 mg, 10 to25 mg, 12 to 30 mg, 20 to 35 mg, 25 to 40 mg, or 30 to 40 mg ofapomorphine, an apomorphine prodrug, or an acid addition salt thereof).For example, each unit dosage form can contain 3±1 mg, 4±1 mg, 5±1 mg,8±2 mg, 10±3 mg, 12±3 mg, 15±3 mg, 22±4 mg, 27±4 mg, 30±5 mg, 35±5 mg,or 40±5 mg of apomorphine, an apomorphine prodrug, or an acid additionsalt thereof.

In another embodiment of any of the above pharmaceutical compositions,the unit dosage form when placed in 1 mL of unbuffered water at pH 7results in a solution having a pH of between 7.4 and 9.1 (e.g., a pH ofbetween 7.4 and 8.8, 7.4 and 8.3, 7.6 and 8.8, 7.6 and 8.5, 8.2 and 8.5,8.4 and 8.7, 8.6 and 8.8, or 8.7 and 9.1).

In still another embodiment of any of the above pharmaceuticalcompositions, following sublingual administration to a subject the unitdosage form produces an average circulating concentration of at least 3ng/mL within a period of from 5 to 15 minutes following theadministration. For example, the unit dosage form can produce an averagecirculating concentration of from 3 to 6 ng/mL within 7 to 10 minutes,from 5 to 10 ng/mL within 5 to 10 minutes, from 7 to 12 ng/mL within 5to 10 minutes, from 10 to 16 ng/mL within 5 to 10 minutes, from 3 to 6ng/mL within 7 to 15 minutes, from 5 to 10 ng/mL within 7 to 15 minutes,from 7 to 12 ng/mL within 7 to 15 minutes, from 10 to 16 ng/mL within 7to 15 minutes, from 3 to 6 ng/mL within 15 to 20 minutes, from 5 to 10ng/mL within 15 to 20 minutes, from 7 to 12 ng/mL within 15 to 20minutes, or from 10 to 16 ng/mL within 15 to 20 minutes following theadministration.

The invention further features a method of treating Parkinson's diseasein a mammal by sublingually administering a pharmaceutical compositionof the invention to the mammal in an amount effective to treat themammal.

The invention also features a method for alleviating dyskinesia in amammal afflicted with Parkinson's disease by sublingually administeringa pharmaceutical composition of the invention to the mammal in an amounteffective to alleviate the dyskinesia.

The invention also features a method for alleviating akinesia in amammal afflicted with Parkinson's disease by sublingually administeringa pharmaceutical composition of the invention to the mammal in an amounteffective to alleviate the akinesia.

The invention features a method of treating sexual dysfunction in amammal by sublingually administering a pharmaceutical composition of theinvention to the mammal in an amount effective to treat the mammal.

The invention also features a method of treating a depressive disorderin a mammal by sublingually administering a pharmaceutical compositionof the invention to the mammal in an amount effective to treat themammal.

In one embodiment of any of the above methods, the method furtherincludes administration of an effective amount of an anti-emetic agent(e.g., nicotine, lobeline sulfate, pipamazine, oxypendyl hydrochloride,ondansetron, buclizine hydrochloride, cyclizine hydrochloride,dimenhydrinate, scopolamine, metopimazine, benzauinamine hydrochloride,or diphenidol hydrochloride).

In an embodiment of any of the above methods and compositions, theapomorphine, apomorphine prodrug, or salt thereof is a racemic mixtureof R and S isomers, or enriched in R isomer (i.e., the ratio of R to Sisomer for all of the apomorphine in the composition, or all theapomorphine being administered, is from 5:1 to 1,000:1, from 10:1 to10,000:1, or from 100:1 to 100,000:1, or over all apomorphine isomers inthe composition is at least 98% R isomer, 99% R isomer, 99.5% R isomer,99.9% R isomer, or is free of any observable amount of S isomer.

The term “administration” or “administering” refers to a method ofgiving a sublingual dosage of apomorphine, or an apomorphine prodrug, toa patient.

As used herein, the term “apomorphine particle” refers to microparticlesor nanoparticles containing apomorphine, an apomorphine prodrug, orsalts thereof.

As used herein, the term “average circulating concentration” refers tothe average plasma concentration of apomorphine at time t observed for agroup of subjects following sublingual administration of a particularunit dosage form of the invention. For example, among 20 subjects theaverage circulating concentration concentration of apomorphine 10minutes following sublingual administration of the unit dosage form canbe at least 3 ng/mL, 5 ng/mL, 7 ng/mL, 9 ng/mL, 11 ng/mL, 13 ng/mL, or15 ng/mL, depending upon the amount of apomorphine in the unit dosage.

By “depressive disorder” is meant any psychological or psychiatricdisorder associated with symptoms of depressed mood. Treatabledepressive disorders may be characterized by an inhibition or reductionof dopaminergic function in the nucleus accumbens, e.g., majordepression, dysthymia, bipolar disorder (manic depression), andpost-traumatic stress disorder.

As used herein, the terms “effective particle size” and “particle size”are used interchangeably and refer to a mixture of particles having adistribution in which 50% of the particles are below and 50% of theparticles are above a defined measurement. The “effective particle size”refers to the volume-weighted median diameter as measured by alaser/light scattering method or equivalent, wherein 50% of theparticles, by volume, have a smaller diameter, while 50% by volume havea larger diameter. The effective particle size can be measured byconventional particle size measuring techniques well known to thoseskilled in the art. Such techniques include, for example, sedimentationfield flow fractionation, photon correlation spectroscopy, lightscattering (e.g., with a Microtrac UPA 150), laser diffraction, and disccentrifugation.

As used herein, the term “apomorphine prodrug” refers to apomorphineesters and glycosides of formula (I):

and acid addition salts thereof. In formula I, each of R¹ and R² is,independently, H, C(O)—R₃, C(O)—O—R₃, or a glycoside of a monosaccharideor oligosaccharide; or R¹ and R² combine with the oxygen atoms to whichthey are bound to form a cyclic acetal, cyclic ketal, a cyclic carbonate(i.e., —C(O)—O—C(O)—), or an orthoester glycoside; and R₃ is a cyclic,straight chained, or branched hydrocarbon of 1 to 12 carbon atoms, whichis optionally saturated (i.e., a C₁₋₁₂ alkyl), includes one or morecarbon-carbon double bonds (i.e., a C₂₋₁₂ alkenyl), and/or includes oneor more carbon-carbon triple bonds (i.e., a C₂₋₁₂ alkynyl). For example,the apomorphine glycosides can be glycosides of straight or branchedchain glycosidic moiety containing 1-20 glycosidic units. Apomorphineglycosides and orthoester glycosides can be synthesized as described inPCT Publication No. WO/2003/080074. Apomorphine esters, cyclic acetals,and cyclic ketals can be synthesized using methods analogous to thosedescribed in U.S. Pat. No. 4,687,773, Borgman et al., J. Med. Chem.,19:717 (1976), and PCT Publication No. WO/2005/099702. The above patentpublications are incorporated herein by reference. Carbonate esters ofapomorphine can be prepared as described in Atkinson et al., J. Pharma.Sci. 65:1685 (1976), and in Campbell et al., Neuropharmacology 21:953(1982). Apomorphine prodrugs which can be used in the unit dosage formsof the invention include, without limitation, O,O′-diacetylapomorphine,O,O′-dipropionylapomorphine, O,O′-diisobutyrylapomorphine,O,O′-dipivaloylapomorphine, O,O′-dibenzoylapomorphine, apomorphinecarbonate, apomorphine diethylcarbonate, apomorphine methylene acetal,apomorphine ethyl acetal, apomorphine dimethyl acetal, and acid additionsalts thereof.

As used herein, “pH neutralizing agent” refers to any basic componentpresent in the unit dosage forms of the invention. The pH neutralizingagents which can be used in the unit dosage forms of the inventioninclude organic bases (e.g., amines), inorganic bases (e.g., oxides,hydroxides, carbonates, or phosphates), and mixtures thereof. The pHneutralizing agent is typically present in an amount sufficient toproduce a solution having a pH of between 7.4 and 9.1 when the unitdosage form is placed in 1 mL of unbuffered water at pH 7.

As used herein, “sexual dysfunction” refers to disorders of orgasm,response timing, ejaculation, nociception, congestive arousal anderection, vasculogenic impairment, or desire. In males, the form ofsexual dysfunction is typically erectile dysfunction, the inability toachieve and sustain an erection sufficient for intercourse. Females alsocan have sexual dysfunctions of arousal and orgasm that increase withage and are associated with the presence of vascular risk factors andonset of menopause. Some of the vascular and muscular mechanisms thatcontribute to penile erection in the male are believed to involvesimilar vasculogenic factors in female genital responses. Female sexualdysfunction includes a failure to attain or maintain vaginallubrication-swelling responses of sexual excitement until completion ofthe sexual activity.

As used herein, the term “treating” refers to administering apharmaceutical composition for prophylactic and/or therapeutic purposes.To “prevent disease” refers to prophylactic treatment of a patient whois not yet ill, but who is susceptible to, or otherwise at risk of, aparticular disease. To “treat disease” or use for “therapeutictreatment” refers to administering treatment to a patient alreadysuffering from a disease to ameliorate the disease and improve thepatient's condition. Thus, in the claims and embodiments, treating isthe administration to a mammal either for therapeutic or prophylacticpurposes.

Other features and advantages of the invention will be apparent from thefollowing detailed description and the claims.

DETAILED DESCRIPTION

The invention features sublingual formulations of apomorphine andapomorphine prodrugs. The formulations can be useful for the treatmentof Parkinson's disease, sexual dysfunction, and depressive disorderstherewith. In certain aspects, the invention features (i) sublingualformulations in unit dosage form having a first portion including anacid addition salt of apomorphine, or an apomorphine prodrug, and asecond portion including a pH neutralizing agent; (ii) sublingualformulations including apomorphine particles having an effectiveparticle size of from 20 nm to 10 μm; and/or (iii) sublingualformulations including protonated apomorphine, or an apomorphineprodrug, complexed to an anionic polyelectrolyte.

Fluctuations in motor disability and dyskinesias are a significantproblem in the long-term treatment of Parkinson's disease. In the laterstages of Parkinson's disease, many patients develop severe “off”episodes where, despite continuing to take their medication, theyexperience periods when they lose the ability to move (e.g., thepatients develop bradykinesia (slowed movement) or akinesia (inabilityto move)). These “off” episodes typically occur 3 to 4 times per day.

Apomorphine has a rapid onset of action which is ideal for use as arescue therapy for intractable “off” periods in Parkinson's disease.

Using the sublingual formulations of the invention, a subject sufferingfrom the effects of middle stage or late stage Parkinson's disease maybe able to recognize the onset of their “off” symptoms and be capable ofadministering a sublingual dose of a formulation of the invention toalleviate the dyskinesia associated with such “off” episodes. Thesublingual formulations are easy for a subject with compromised motorskills to administer and can relieve a Parkinson's patient from the needfor a caregiver, who might otherwise be needed to administer aninjectable dosage form of apomorphine at the onset of an “off” episode.

The sublingual formulations of the invention can increase thebioavailability of apomorphine, prolong the stability of apomorphine,and/or improve the safety and efficacy of apomorphine therapy. Theformulations can produce a rapid uptake of apomorphine into the subject,allowing dyskinesia episodes to be self-treated. Furthermore, theconvenience with which these sublingual formulations can be selfadministered provides a significant advantage to severely ill patients,such as those with middle stage or late stage Parkinson's disease.

Additional details of how to make and use the sublingual formulations ofthe invention are provided below and in the Examples.

Monolayer and Bilayer Films

The films of the invention are not dissimilar to the films used, forexample, to make the Listerine® PocketPak® mouth fresheners. InPocketPak films the polymers used are typically polysaccharide-based orpolysaccharide and glycoprotein-based gums such as pullulan, pectin,locust bean gum, xanthan gum, sodium alginate, gum Arabic and the like.These same polymers can be used in the films of the invention.

The films can include one layer, two layers, or more. If in two layers,the one adapted to adhere to mucosal tissue may be referred to as the“adhesive layer.” With two layers, the outer layer can be less adhesiveor non-adhesive, and can provide protection against mechanicalagitation, such as agitation by a user's tongue. The components of theouter layer might be, of themselves, less dissolvable than thecomponents of an adhesive layer. However, in the aggregate, the filmshall dissolve in that it will transition to fully dissolved parts orparts that will be carried away by normal cleaning processes at themucosal tissue in question. In forming two layers, diffusion or theforming process itself may provide a gradient in component amounts inthe transition between the two layers. The two layers can be utilized toseparate components (e.g., an apomorphine-containing, or an apomorphineprodrug-containing, acidic layer and a buffered pH neutralizing layer),which together enhance absorption of the apomorphine, or apomorphineprodrug, but are otherwise incompatible in a formulation requiring longterm stability (i.e., shelf life). Alternatively, the unit dosage formof the invention can be a monolayer film that is anapomorphine-containing, or an apomorphine prodrug-containing, acidiclayer which is coated with or impregnated with a particulate base. Theparticulate base can be incorporated into the monolayer film using themethods described in PCT Publication No. WO/2009/052421, U.S. PatentPublication No. 20060210610, each of which is incorporated herein byreference. The film of the invention can include an effervescentparticulate (i.e., a particulate carbonate base). Such effervescentfilms can be prepared as described in U.S. Patent Publication No.20010006677, incorporated herein by reference.

The polymers used in the films of the invention can be polymers thataffect the rate of hydration or mucosal adhesion properties of anadhesive layer. Such polymers can be, for example,carboxymethylcellulose, cellulose acetate, ethylcellulose,hydroxyethylcellulose, hydroxypropylmethylcellulose (HPMC, such asPharmacoat 606™, Shin-Etsu Chemical Company Ltd., Japan),nitrocellulose, polyoxyethylene/polyoxypropylene polymers, copolymers orblock copolymers, polyvinylpyrrolidone polymers or derivatives, andgums. The average molecular weight of the polymer can be selected basedon the swelling and dissolution profile sought. Mixtures of less solubleand/or less swellable polymers with more soluble or swellable polymerscan help transition the film to a sufficiently dissolved form. Forexample, the film can include carbamer, polyethylene oxide,ethylcellulose, titanium oxide and colorant (such as F, D and C bluelake colorant). Often the film is formed using a pharmaceuticallyappropriate solvent such as ethanol, water, mixtures, or the like. Suchsolvents are typically largely evaporated away prior to use. Optionally,the films comprise a blend of more than one polymers or more than onemolecular weight of a given set of polymers in order to control the rateof hydration, physical properties and mechanical properties.

Basic Layers

The multi-layered films of the invention can include a film formed froma basic polymer. Polyamines which can be used in the unit dosage formsof the invention include homo and copolymers ofdimethylaminoethyl-acrylate, dimethylaminoethyl-methacrylate,dimethylaminopropyl-acrylate, dimethylaminpropyl-methacrylate, or othersimilar amino-functionalized acrylate, chitosan or partially hydrolyzedchitin in a substantially basic form, homo and co polymers ofpolyethyleimine, polylysine, polyvinylimidazole, or polyvinylamine. Incertain embodiments the polyamine is Eudragit E100.

Other Components

Plasticizers, penetration enhancers, flavoring agents, preservatives,odorants, coloring agents, and the like can be included in the unitdosage forms of the invention.

Plasticizers will generally modify the feel, softness, flexibility (inan un-wetted state) of the unit dosage forms of the invention.Penetration enhancers may, in some cases, act as plasticizers. Examplesof plasticizers include, without limitation, glycerol, propylene glycol,fatty acid esters, such as glyceryl oleate, polyalcohols, sorbitanesters, citric acid esters, polyethylene glycol (e.g., PEG 400),polyvinyl alcohol, polyvinyl methyl ether, triacetin; mannitol, xylitol,and sorbitol. The plasticizer can be present in any suitable range,including, for example about 0.5% to 30%, 10% to 20%, or 15% to 18% byweight of the dry film.

Permeation enhancers can be used to improve the permeability of theapomorphine at the mucosal membrane in the unit dosage forms of theinvention. One or more permeation enhancers maybe used to modulate therate of mucosal absorption of the apomorphine. Any effective permeationenhancers may be used including, for example, bile salts, such as sodiumcholate, sodium glycocholate, sodium glycodeoxycholate,taurodeoxycholate, sodium deoxycholate, sodium lithocholatechenocholate, chenodeoxycholate, ursocholate, ursodeoxy-cholate,hyodeoxycholate, dehydrocholate, glycochenocholate, taurochenocholate,and taurochenodeoxycholate; sodium dodecyl sulfate (SDS), dimethylsulfoxide (DMSO), N-lauroyl sacrcosine, sorbitan monolaurate, stearylmethacrylate, N-dodecylazacycloheptan-2-one, N-dodecyl-2-pyrrolidinone,N-dodecyl-2-piperidinone, 2-(1-nonyl)-1,3-dioxolane, N-(2-methoxymethyl)dodecylamine, N-dodecylethanolamine,N-dodecyl-N-(2-methoxymethyl)acetamide,1-N-dodecyl-2-pyrrolidone-5-carboxylic acid,2-pentyl-2-oxo-pyrrolidineacetic acid,2-dodecyl-2-oxo-1-pyrrolidineacetic acid,2-dodecyl-2-oxo-1-pyrrolidineacetic acid,1-azacylioheptan-2-one-dodecylacetic acid, menthol, propylene glycol,glycerol monostearate, sorbitol monolaurate, glycerol dilaurate,tocopherol acetate, phosphatidyl choline, glycerol, polyethyleneglycol,monoglycerides, diglycerides, triglycerides, lecithin, tweensurfactants, sorbitan surfactants, sodium lauryl sulfate; salts andother derivatives of saturated and unsaturated fatty acids, surfactants,bile salt analogs, derivatives of bile salts, or such syntheticpermeation enhancers as described in U.S. Pat. No. 4,746,508, which isincorporated herein by reference.

A flavoring agent and/or odorant can be added to the unit dosage formsof the invention to make them more palatable. At least one flavoringagent or odorant composition may be used. Any effective flavor or odormay be rendered. The flavoring agents may be natural, artificial, or amixture thereof. The flavoring agent gives a flavor that is attractiveto the user. In one embodiment, the flavoring agent may give the flavorof mint, honey lemon, orange, lemon lime, grape, cranberry, vanillaberry, Magnasweet™, bubble gum, or cherry. The flavoring agent can benatural or artificial sweetener, such as sucrose, xylitol, sodiumsaccharin, cyclamate, aspartame, acesulfame, and salts thereof.

Apomorphine is susceptible to oxidative degradation. To minimizeoxidative degradation it is desirable that the formulations of theinvention contain one or more antioxidants. Antioxidants that can beused in the films of the invention can be selected from thiols (e.g.,aurothioglucose, dihydrolipoic acid, propylthiouracil, thioredoxin,glutathione, cysteine, cystine, cystamine, thiodipropionic acid),sulphoximines (e.g., buthionine-sulphoximines,homo-cysteine-sulphoximine, buthionine-sulphones, and penta-, hexa- andheptathionine-sulphoximine), metal chelators (e.g, α-hydroxy-fattyacids, palmitic acid, phytic acid, lactoferrin, citric acid, lacticacid, and malic acid, humic acid, bile acid, bile extracts, bilirubin,biliverdin, EDTA, EGTA, and DTPA), sodium metabisulfite, vitamins (e.g.,vitamin E, vitamin C, ascorbyl palmitate, Mg ascorbyl phosphate, andascorbyl acetate), phenols (e.g., butylhydroxytoluene,butylhydroxyanisole, ubiquinol, nordihydroguaiaretic acid,trihydroxybutyrophenone), benzoates (e.g., coniferyl benzoate), uricacid, mannose, propyl gallate, selenium (e.g., selenium-methionine),stilbenes (e.g., stilbene oxide and trans-stilbene oxide), andcombinations thereof. The total amount of antioxidant included in thefilms can be from 0.001% to 3% by weight, preferably 0.01% to 1% byweight, in particular 0.05% to 0.5% by weight, based on the total weightof the formulation.

In certain embodiments, the various components (e.g., plasticizers,penetration enhancers, flavoring agents, preservatives, odorants,coloring agents, particulate base, and apomorphine particles) includedin the unit dosage forms of the invention can be combined andincorporated into a first portion that is acidic and includes theapomorphine, or a prodrug thereof, or combined and incorporated into asecond portion that is basic and includes a pH neutralizing component,or the components may be divided between the two portions. In someinstances it may be desirable to minimize interaction between the acidicportion of the unit dosage form and the basic portion of the unit dosageform by including a barrier between the two. For example, a barrier canbe included in the unit dosage forms of the invention as a third layerinterposed between the acidic layer and the basic layer of a multilayersublingual dosage form. Alternatively, the barrier can be a rapidlydissolving coating on the surface of a particulate component in the unitdosage form, such as a coated particulate base coated onto, or embeddedwithin, an acidic portion of the unit dosage form. In still anotherapproach, the barrier can be a rapidly dissolving coating on the surfaceof apomorphine particles in the unit dosage form, which further includesa basic portion. These approaches can be utilized to ensure that theapomorphine-containing, or an apomorphine prodrug-containing, acidicportion of the unit dosage form is not neutralized prior to theadministration to a subject.

Apomorphine Particles

The pharmaceutical formulations described herein can include apomorphineparticles having an effective particle size of from about 1 micron toabout 10 microns. The starting apomorphine composition can bepredominantly crystalline, predominantly amorphous, or a mixturethereof, and can include unmodified apomorphine or an apomorphineprodrug.

In an alternative approach, the pharmaceutical formulations describedherein can include apomorphine particles having an effective particlesize of less than about 1 micron (i.e., nanoparticulate formulations).The starting apomorphine composition can be predominantly crystalline,predominantly amorphous, or a mixture thereof, and can includeunmodified apomorphine or an apomorphine prodrug.

These apomorphine particles can be made by using any method known in theart for achieving the desired particle sizes. Useful methods include,for example, milling, homogenization, supercritical fluid fracture, orprecipitation techniques. Exemplary methods are described in U.S. Pat.Nos. 4,540,602; 5,145,684; 5,518,187; 5,718,388; 5,862,999; 5,665,331;5,662,883; 5,560,932; 5,543,133; 5,534,270; and 5,510,118; 5,470,583,each of which is specifically incorporated by reference.

Milling to Obtain Submicron Apomorphine Particles

In one approach, the apomorphine, an apomorphine prodrug, or a saltthereof, is milled in order to obtain micron or submicron particles. Themilling process can be a dry process, e.g., a dry roller millingprocess, or a wet process, i.e., wet-grinding. A wet-grinding process isdescribed in U.S. Pat. Nos. 4,540,602, 5,145,684, 6,976,647 and EPO498,482, the disclosures of which are hereby incorporated by reference.Thus, the wet grinding process can be practiced in conjunction with aliquid dispersion medium and dispersing or wetting agents such asdescribed in these publications. Useful liquid dispersion media includesafflower oil, ethanol, n-butanol, hexane, or glycol, among otherliquids selected from known organic pharmaceutical excipients (see U.S.Pat. Nos. 4,540,602 and 5,145,684), and can be present in an amount of2.0-70%, 3-50%, or 5-25% by weight based on the total weight of theapomorphine, or apomorphine prodrug, in the formulation.

The grinding media for the particle size reduction step can be selectedfrom rigid media, typically spherical in shape, though non-sphericalgrinding media could also be used. The grinding media preferably canhave a mean particle size from 1 mm to about 500 microns. For finegrinding, the grinding media particles can have a mean particle sizefrom about 0.05 to about 0.6 mm. Smaller size grinding media will resultin smaller size apomorphine particles as compared to the same conditionsusing larger sized grinding media. In selecting material, grinding mediawith higher density, e.g., glass (2.6 g/cm³), zirconium silicate (3.7g/cm³), and zirconium oxide (5.4 g/cm³) and 95% zirconium oxidestabilized with yttrium, can be utilized for more efficient milling.Alternatively, polymeric grinding media can be used. Polymeric resinssuitable for use herein are chemically and physically inert,substantially free of metals, solvent and monomers, and of sufficienthardness and friability to enable them to avoid being chipped or crushedduring grinding. Suitable polymeric resins include, without limitation,crosslinked polystyrenes, such as polystyrene crosslinked withdivinylbenzene, styrene copolymers, polycarbonates, polyacetals, such asDelrin™, vinyl chloride polymers and copolymers, polyurethanes,polyamides, poly(tetrafluoroethylenes), e.g., Teflon™, and otherfluoropolymers, high density polyethylenes, polypropylenes, celluloseethers and esters such as cellulose acetate, polyhydroxymethacrylate,polyhydroxyethyl acrylate, and silicone containing polymers such aspolysiloxanes.

Grinding can take place in any suitable grinding mill. Suitable millsinclude an airjet mill, a roller mill, a ball mill, an attritor mill, avibratory mill, a planetary mill, a sand mill and a bead mill. A highenergy media mill is preferred when small particles are desired. Themill can contain a rotating shaft.

The preferred proportions of the grinding media, apomorphine orapomorphine prodrug, the optional liquid dispersion medium, anddispersing, wetting or other particle stabilizing agents present in thegrinding vessel can vary within wide limits and depend on, for example,the size and density of the grinding media, the type of mill selected,the time of milling, etc. The process can be carried out in acontinuous, batch or semi-batch mode. In high energy media mills, it canbe desirable to fill 80-95% of the volume of the grinding chamber withgrinding media. On the other hand, in roller mills, it frequently isdesirable to leave the grinding vessel up to half filled with air, theremaining volume comprising the grinding media and the liquid dispersionmedia, if present. This permits a cascading effect within the vessel onthe rollers which permits efficient grinding. However, when foaming is aproblem during wet grinding, the vessel can be completely filled withthe liquid dispersion medium or an anti-foaming agent may be added tothe liquid dispersion.

The attrition time can vary widely and depends primarily upon themechanical means and residence conditions selected, the initial anddesired final particle size, among other factors. For roller mills,processing times from several days to weeks may be required. On theother hand, milling residence times of less than about 2 hours aregenerally required using high energy media mills. After attrition iscompleted, the grinding media is separated from the milled apomorphineparticulate product (in either a dry or liquid dispersion form) usingconventional separation techniques, such as by filtration, or sievingthrough a mesh screen.

To produce apomorphine particles having an effective particle size ofless than about 1 micron, the grinding media can be made from beadshaving a size ranging from 0.05 mm to 4 mm. For example, high energymilling of apomorphine, or an apomorphine prodrug, with yttriumstabilized zirconium oxide 0.4 mm beads for a milling residence time of25 minutes to 1.5 hours in recirculation mode at 1200 to 3000 RPM. Inanother approach, high energy milling of apomorphine, or an apomorphineprodrug, with 0.1 mm zirconium oxide balls for a milling residence timeof 2 hours in batch mode can be used. The milling concentration can befrom about 10% to about 30% apomorphine, or apomorphine prodrug, byweight in comparison to the milling slurry weight, which can contain awetting and/or dispersing agent to coat the initial suspension so auniform feed rate may be applied in continuous milling mode.Alternatively, batch milling mode is utilized with a milling mediacontaining an agent to adjust viscosity and/or provide a wetting effectso that the apomorphine, or apomorphine prodrug, is well dispersedamongst the grinding media.

Microprecipitation to Obtain Apomorphine Nanoparticles

Apomorphine particles can also be prepared by homogeneous nucleation andprecipitation in the presence of a wetting agent or dispersing agentusing methods analogous to those described in U.S. Pat. Nos. 5,560,932and 5,665,331, which are specifically incorporated by reference. Such amethod can include the steps of: (1) dispersing apomorphine, or anapomorphine prodrug, in a suitable liquid media; (2) adding the mixturefrom step (1) to a mixture including at least one dispersing agent orwetting agent such that at the appropriate temperature, the apomorphine,or an apomorphine prodrug, is dissolved; and (3) precipitating theformulation from step (2) using an appropriate anti-solvent. The methodcan be followed by removal of any formed salt, if present, by dialysisor filtration and concentration of the dispersion by conventional means.In one embodiment, the apomorphine particles are present in anessentially pure form and dispersed in a suitable liquid dispersionmedia. In this approach the apomorphine particles are a discrete phasewithin the resulting mixture. Useful dispersing agents, wetting agents,solvents, and anti-solvents can be experimentally determined.

Homogenization to Obtain Apomorphine Nanoparticles

Apomorphine particles can also be prepared by high pressurehomogenization (see U.S. Pat. No. 5,510,118). In this approachapomorphine particles are dispersed in a liquid dispersion medium andsubjected to repeated homogenization to reduce the particle size of theapomorphine particles to the desired effective average particle size.The apomorphine particles can be reduced in size in the presence of atleast one or more dispersing agents or wetting agents. Alternatively,the apomorphine particles can be contacted with one or more dispersingagents or wetting agents either before or after attrition. Othermaterials, such as a diluent, can be added to the apomorphine/dispersingagent mixture before, during, or after the size reduction process. Forexample, unprocessed apomorphine, or an apomorphine prodrug, can beadded to a liquid medium in which it is essentially insoluble to form apremix (i.e., about 0.1-60% w/w apomorphine, or apomorphine prodrug, andabout 20-60% w/w dispersing agents or wetting agents). The apparentviscosity of the premix suspension is preferably less than about 1000centipoise. The premix can then be transferred to a microfluidizer andcirculated continuously first at low pressures, and then at maximumcapacity (i.e., 3,000 to 30,000 psi) until the desired particle sizereduction is achieved. The resulting dispersion of apomorphine particlescan be spray coated onto a sublingual pharmaceutical formulation of theinvention using techniques well known in the art.

Milling with Simethicone

Foaming during the nanosizing can present formulation issues and canhave negative consequences for particle size reduction. For example,high levels of foam or air bubbles in the mill can cause a drasticincrease in viscosity rendering the milling process inoperable. Even avery low level of air presence can dramatically reduce millingefficiency causing the desired particle size unachievable. This may bedue to the resultant air in the mill cushioning the milling balls andlimiting grinding efficiency. The air also can form a microemulsion withthe milled ingredients which presents many issues with respect to thedelivery of an accurate dose and palatability. Addition of a smallamount of simethicone is a very effective anti-foaming agent whichminimizes milling variability or special handling techniques to avoidthe introduction of air into the milling process.

The Use of Wetting and Dispersing Agents

The apomorphine particles can be prepared with the use of one or morewetting and/or dispersing agents, which are, e.g., adsorbed on thesurface of the apomorphine particle. The apomorphine particles can becontacted with wetting and/or dispersing agents either before, during orafter size reduction. Generally, wetting and/or dispersing agents fallinto two categories: non-ionic agents and ionic agents. The most commonnon-ionic agents are excipients which are contained in classes known asbinders, fillers, surfactants and wetting agents. Limited examples ofnon-ionic surface stabilizers are hydroxypropylmethylcellulose,polyvinylpyrrolidone, Plasdone, polyvinyl alcohol, Pluronics, Tweens andpolyethylene glycols (PEGs). Ionic agents are typically organicmolecules bearing an ionic bond such that the molecule is charged in theformulation, such as long chain sulfonic acid salts (e.g., sodium laurylsulfate and dioctyl sodium sulfosuccinate).

Excipients, such as wetting and dispersing agents, can be applied to thesurface of the apomorphine nanoparticulate via spray drying, spraygranulation, or spray layering process. These procedures are well knownin those skilled in the art. It is also common to add additionalexcipients prior to removal of solvent in the nanoparticulate suspensionto aid in the dispersion of the solid composition in medium in which thesolid composition will be exposed (e.g. saliva) to further preventagglomeration and/or particle size growth of the small apomorphineparticles. An example of such an additional excipient is a redispersingagent. Suitable redispersing agents include, without limitation, sugars,polyethylene glycols, urea and quarternary ammonium salts.

Therapy

Representative examples of diseases and conditions treatable using thesublingual formulations of the invention are as listed hereinabove, andinclude, but are not limited to, Parkinson's disease, sexualdysfunction, and depressive disorders, such as major depression andbipolar disorder.

Sublingual formulations of the invention include rapidly disintegratingor dissolving dosage forms, also known as fast dissolve, fast or rapidmelt, and quick disintegrating dosage forms. These dosage forms dissolveor disintegrate rapidly in the patient's mouth without chewing or theneed for water within a short time frame. Because of their ease ofadministration, such compositions are particularly useful for thespecific needs of patients with compromised motor skills. The sublingualformulations may be in unit dosage form in the shape of, for example, alozenge, a pill, a tablet, a film, or a strip. Alternatively, thesublingual formulations may be prepared in non-unit dosage forms, suchas a gel.

The apomorphine, or apomorphine prodrug, may be administered in its freebase form or as a pharmaceutically acceptable salt, such as a non-toxicacid addition salts or metal complexes that are commonly used in thepharmaceutical industry. Examples of acid addition salts include organicacids such as acetic, lactic, pamoic, maleic, citric, malic, ascorbic,succinic, benzoic, palmitic, suberic, salicylic, tartaric,methanesulfonic, toluenesulfonic, or trifluoroacetic acids or the like;polymeric acids such as tannic acid, carboxymethyl cellulose, alginicacid, or the like; and inorganic acid such as hydrochloric acid,hydrobromic acid, sulfuric acid phosphoric acid, or the like. Metalcomplexes include calcium, zinc, iron, and the like. In certaininstances the formulation of the invention includes apomorphinehydrochloride, or the hydrochloride salt of or an apomorphine prodrug.

The formulations can be administered to patients in therapeuticallyeffective amounts. For example, an amount is administered whichprevents, reduces, or eliminates the symptoms of Parkinson's disease,sexual dysfunction, or depression, respectively. Typical dose ranges arefrom about 2 mg to about 30 mg of apomorphine, or a salt thereof, givenup to five times per day. The exemplary dosage of apomorphine, orapomorphine prodrug, to be administered is likely to depend on suchvariables as the type and extent of the condition, the overall healthstatus of the particular patient, the particular form of apomorphinebeing administered, and the particular sublingual formulation beingused.

Potential adverse effects can be ameliorated by administeringapomorphine, or an apomorphine prodrug, in combination with ananti-emetic agent, such as nicotine, lobeline sulfate, pipamazine,oxypendyl hydrochloride, ondansetron, buclizine hydrochloride, cyclizinehydrochloride, dimenhydrinate, scopolamine, metopimazine, benzauinaminehydrochloride or diphenidol hydrochloride. In certain instances it maybe desirable to incorporate the anti-emetic into the sublingualformulation for simultaneous administration in combination withapomorphine, or apomorphine prodrug.

The following examples are put forth so as to provide those of ordinaryskill in the art with a complete disclosure and description of how themethods and compounds claimed herein are performed, made, and evaluated,and are intended to be purely exemplary of the invention and are notintended to limit the scope of what the inventors regard as theirinvention.

Example 1 Two Layer Apomorphine Strip

Preparation of the First Layer:

Gelatin and mannitol are dispersed in purified water and mixedthoroughly (i.e., using a vacuum mixer) and homogenized. Apomorphinehydrochloride is added and the mixture was again homogenized to ensurecomplete dissolution of the apomorphine hydrochloride. The pH of thesolution is adjusted to about 3.0 (i.e., by addition of a suitable acid,such as citric acid). The solution is then poured onto a sheet and driedin a heated oven.

Preparation of the Second Layer:

Ethyl cellulose, poly(ethylene oxide), and hydroxypropylcellulose aredissolved in anhydrous ethanol. To the resulting solution is added a pHmodifying agent (i.e., calcium hydroxide, magnesium hydroxide, potassiumhydroxide, sodium hydroxide, calcium carbonate, iron carbonate,magnesium carbonate, zinc carbonate, sodium acetate, sodium carbonate,potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodiumphosphate monobasic, sodium phosphate dibasic, sodium phosphatetribasic, potassium phosphate monobasic, potassium phosphate dibasic,potassium phosphate tribasic, and mixtures thereof). Alternatively, thepH modifying agent can be a polyamine, such as Eudragit E100.

A solvent-cast mucoadhesive film is prepared by casting a thin film ofthe solution onto the first layer. Evaporation of the solvent (ethanol)can be accomplished by drying at 60° C. for 30 minutes.

The resultant dry film includes (i) a first acidic layer containingapomorphine in a stable acid addition salt form (i.e., the hydrochloridesalt), and (ii) a second basic layer (the adhesive layer) capable ofneutralizing some of the apomorphine at the time of sublingualadministration. The two layer film can enhance the bioavailability ofthe apomorphine, as absorption is enhanced when apomorphinehydrochloride is neutralized, without compromising the shelf lifestability of the film.

The two-layer film is cut into strips, each strip containing theequivalent of from 2 mg to 20 mg of apomorphine in its free base form.The strips can be administered to a subject for the treatment ofParkinson's disease, sexual dysfunction, or depressive disorders.

Example 2 Single Layer Nanoparticulate Apomorphine Strip

Ethyl cellulose, poly(ethylene oxide), and hydroxypropylcellulose aredissolved in anhydrous ethanol to form a solution.

Nanoparticulate apomorphine hydrochloride is prepared by milling solidapomorphine hydrochloride as described herein.

The particulate apomorphine is suspended in the solution and asolvent-cast mucoadhesive film is prepared by casting a thin film of themixture onto a sheet. Evaporation of the solvent (ethanol) can beaccomplished by drying at 60° C. for 30 minutes.

The resultant dry film includes a single adhesive layer that releasesnanoparticulate apomorphine. The apomorphine can penetrate the mucosaltissue in its nanoparticulate form, thus enhancing the bioavailabilityof the apomorphine in the film.

The single-layer nanoparticulate film is cut into strips, each stripcontaining the equivalent of from 2 mg to 20 mg of apomorphine in itsfree base form. The strips can be administered to a subject for thetreatment of Parkinson's disease, sexual dysfunction, or depressivedisorders.

Example 3 Single Layer Apomorphine Free Base Strip

All materials are degassed prior to use and all steps are carried outunder a nitrogen atmosphere.

Ethyl cellulose, poly(ethylene oxide), and hydroxypropylcellulose aredissolved in anhydrous ethanol to form a polymer solution.

The apomorphine hydrochloride and an antioxidant (e.g., sodiummetabisulfite) are dissolved in a minimal amount of water and added tothe polymer solution. The pH of the resulting mixture is adjusted toabout 9.0 (i.e., by addition of a suitable base, such as sodiumhydroxide).

A solvent-cast mucoadhesive film is prepared by casting a thin film ofthe mixture onto a sheet. Evaporation of the solvent (ethanol/water) canbe accomplished by drying at 60° C. for 30 minutes, and/or drying underreduced pressure.

The resultant dry film includes a single adhesive layer that releasesfree base apomorphine. The apomorphine can penetrate the mucosal tissuein its nanoparticulate form, thus enhancing the bioavailability of theapomorphine in the film.

The single-layer film is cut into strips, each strip containing theequivalent of from 2 mg to 20 mg of apomorphine in its free base form.The strips can be administered to a subject for the treatment ofParkinson's disease, sexual dysfunction, or depressive disorders.

Example 4 Two-Layer Apomorphine-Anionic Polyelectrolyte Complex

Preparation of the First Layer:

Apomorphine (free base) is combined with alginic acid to form anapomorphine-alginate complex. To the complex is added gelatin, mannitol,and purified water. The mixture is mixed thoroughly (i.e., using avacuum mixer) and homogenized. The pH of the solution is adjusted toabout 3.0. The solution is then poured onto a sheet and dried in aheated oven.

Preparation of the Second Layer:

Ethyl cellulose, poly(ethylene oxide), and hydroxypropyl cellulose aredissolved in anhydrous ethanol. To the resulting solution is added a pHmodifying agent (i.e., calcium hydroxide, magnesium hydroxide, potassiumhydroxide, sodium hydroxide, calcium carbonate, iron carbonate,magnesium carbonate, zinc carbonate, sodium acetate, sodium carbonate,potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodiumphosphate monobasic, sodium phosphate dibasic, sodium phosphatetribasic, potassium phosphate monobasic, potassium phosphate dibasic,potassium phosphate tribasic, and mixtures thereof). Alternatively, thepH modifying agent can be a polyamine, such as Eudragit E100.

A solvent-cast mucoadhesive film is prepared by casting a thin film ofthe solution onto the first layer. Evaporation of the solvent (ethanol)can be accomplished by drying at 60° C. for 30 minutes.

The resultant dry film includes (i) a first acidic layer containingapomorphine in a stable acid addition salt complex with alginic acid,and (ii) a second basic layer (the adhesive layer) capable ofneutralizing some of the apomorphine at the time of sublingualadministration. The two layer film can enhance the bioavailability ofthe apomorphine, as absorption is enhanced when apomorphine isneutralized, without compromising the shelf life stability of the film.

The two-layer film is cut into strips, each strip containing theequivalent of from 2 mg to 20 mg of apomorphine in its free base form.The strips can be administered to a subject for the treatment ofParkinson's disease, sexual dysfunction, or depressive disorders.

Example 5 Nanoparticulate Apomorphine Gel

Nanoparticulate apomorphine hydrochloride is prepared by milling solidapomorphine hydrochloride as described herein.

The particulate apomorphine is combined with sodiumcarboxymethylcellulose and glycerol. The resulting mixture is mixedthoroughly (i.e., using a vacuum mixer) and homogenized. Water is addedto the mixture (with extensive mixing) to form a hydrogel containingsuspended nanoparticles of apomorphine hydrochloride.

The nanoparticulate gel can be dispensed under the tongue in amountscontaining the equivalent of from 2 mg to 20 mg of apomorphine in itsfree base form. The gel can be administered to a subject for thetreatment of Parkinson's disease, sexual dysfunction, or depressivedisorders.

Example 6 Apomorphine-Anionic Polyelectrolyte Complex Gel

Apomorphine (free base) is combined with alginic acid to form anapomorphine-alginate complex.

The apomorphine-alginate complex is combined with sodiumcarboxymethylcellulose, glycerol, and an antioxidant (e.g., sodiummetabisulfite). The resulting mixture is mixed thoroughly (i.e., using avacuum mixer) and homogenized. Water is added to the mixture (withextensive mixing) to form a hydrogel containing apomorphine-alginatecomplex.

The gel can be dispensed under the tongue in amounts containing theequivalent of from 2 mg to 20 mg of apomorphine in its free base form.The gel can be administered to a subject for the treatment ofParkinson's disease, sexual dysfunction, or depressive disorders.

Example 7 Bilayer Apomorphine with Polymer-Based Neutralizer

The following ingredients are mixed with 200 parts 2-1 water-ethanolsolvent in an oxygen free environment: 40 parts apomorphinehydrochloride, 5 parts citric acid, 7 parts Methocel E5, 18 partsMethocel E50, 3 parts Klucel JF, 6 parts Sucralose, 3 parts PEG400, 3parts sorbitol, 1 Prosweet G, 4 parts maltodextrin M180, 4 parts IPCB792, and 6 parts spearmint. The mixture is spread on a thin plasticliner and dried to produce a film of ca. 40 μm thickness.

Separately, Eudragit E100 is dissolved to form a viscous mixture inethanol and acetone 1:1. The mixture is spread on a thin plastic linerto produce a film of ca. 24 μm thickness.

The apomorphine layer is fused to the Eudragit layer using heat (60° C.)and pressure to create a bilayer film. Individual dosing units of 40 mgapomorphine hydrochloride are obtained by cutting the film to 2.5×1 cm.

Example 8 Tablet with Apomorphine and Basic Agent

The following ingredients are blended: 40 parts apomorphinehydrochloride jet-milled to 10 μm (D95), 100 parts lactose, 100 partsmicrocrystalline cellulose, 5 parts sodium phosphate dibasic, 25 partscrosslinked povidone, 18 parts sucralose, 2 parts colloidal silica, 5parts mint flavoring, and 5 parts magnesium stearate. Tablets of 300 mgare pressed to provide tablets containing 40 mg of apomorphine.

Alternatively, the present ingredients can be segregated into anapomorphine containing mixture and second, sodium phosphate mixture,which are pressed into a bilayer tablet.

Example 9 Dispersed Milled Apomorphine in Bilayer Thin Film

According to methods of a previous example, jet-milled powder ofapomorphine hydrochloride (D95<10 μm) is added to a mixture ofpolyethyleneglycol, polyprrolidone, sucralose, sorbitol and xylitol inethanol-ethylacetate to create a homogeneous dispersion of the activeingredient. The mixture is spread on a thin plastic liner and dried toproduce a film of ca. 40 μm thickness. This film can be administered asis or combined with a neutralizing layer as per previous examples. Alsocontemplated, is the addition of jet-milled sodium carbonate to thedispersion of ingredient prior to drying to create a single layerwherein both active apomorphine hydrochloride and a neutralizing agentare dispersed as solid agents within a single layer.

Example 10 Hard Candy Lozenge

A candy matrix is formed by mixing one cup (240 grams) of sugar, ⅓ cup(81 cc) of light corn syrup, and slightly more than 1 cup (240 ml) ofwater. The matrix mixture is heated to a temperature of at least 285°F., taking care to avoid stirring the mixture at temperatures greaterthan 200° F. to prevent uncontrolled crystallization of the sugarmixture. The matrix mixture is allowed to cool to 260° F., and 4 ml of aflavoring agent and ⅛ teaspoon (0.625 cc) of citric acid are added,followed by the addition of 900 mg of milled apomorphine HCl and 1800 mgsodium phosphate dibasic. These ingredients are stirred thoroughly intothe matrix, and the resulting mixture is poured into molds which havebeen sprayed with an anti-stick coating (e.g., sprayed with theanti-stick coating known under the trademark PAM). Sticks are inserted 2minutes after pouring into the molds. Desirably, the hard candy lozengeis prepared under an inert atmosphere to minimize oxidation of theapomorphine.

It should be noted that the mixture contains no die, no alcohol, nosynthetic flavor agents and no preservatives, and is completely natural.

Example 11 Monolayer Apomorphine with Particulate Base Neutralizer

The following ingredients are mixed with 200 parts 2-1 water-ethanolsolvent in an oxygen free environment: 40 parts apomorphinehydrochloride, 5 parts citric acid, 7 parts Methocel E5, 18 partsMethocel E50, 3 parts Klucel JF, 6 parts Sucralose, 3 parts PEG400, 3parts sorbitol, 1 Prosweet G, 4 parts maltodextrin M180, 4 parts IPCB792, and 6 parts spearmint. The mixture is spread on a thin plasticliner and dried to produce a film of ca. 40 μm thickness.

Separately, a pH neutralizing solid (e.g., sodium carbonate, potassiumcarbonate, sodium bicarbonate, potassium bicarbonate, sodium phosphatemonobasic, sodium phosphate dibasic, sodium phosphate tribasic,potassium phosphate monobasic, potassium phosphate dibasic, potassiumphosphate tribasic, or mixtures thereof) is milled to produce amicroparticulate base. That the neutralizing solid is optionally coatedwith a neutral barrier, such as polyethylene glycol.

The apomorphine layer is coated with the microparticulate base, forexample, by electrospray or static spray application. Optionally, thelayer may be heated (ca. 60° C.) and the microparticulate base pressedinto the apomorphine layer to form a monolayer film containing a solidsolution of apomorphine hydrochloride with a microparticulate basedispersed within the film. Individual dosing units of 40 mg apomorphinehydrochloride are obtained by cutting the film to 2.5×1 cm.

Other Embodiments

All publications, patents, and patent applications mentioned in thisspecification are herein incorporated by reference to the same extent asif each independent publication or patent application was specificallyand individually indicated to be incorporated by reference.

While the invention has been described in connection with specificembodiments thereof, it will be understood that it is capable of furthermodifications and this application is intended to cover any variations,uses, or adaptations of the invention following, in general, theprinciples of the invention and including such departures from thepresent disclosure that come within known or customary practice withinthe art to which the invention pertains and may be applied to theessential features hereinbefore set forth, and follows in the scope ofthe claims.

Other embodiments are within the claims.

What is claimed is: 1.-2. (canceled)
 3. A method of treating Parkinson'sdisease in a subject in need thereof, the method comprising: (i)providing a pharmaceutical composition in unit dosage form that is afilm having a first portion comprising apomorphine particles comprisingan acid addition salt of apomorphine and a second portion comprising apH neutralizing agent, wherein the film comprises the acid addition saltof apomorphine in an amount effective to treat Parkinson's disease; and(ii) administering the film by placing the film sublingually in themouth of the subject and contacting sublingual mucosal tissue with thefilm.
 4. The method of claim 3, wherein the acid addition salt ofapomorphine is apomorphine hydrochloride.
 5. The method of claim 3,wherein the film further comprises an antioxidant.
 6. The method ofclaim 3, wherein the film further comprises a permeation enhancer. 7.The method of claim 6, wherein the permeation enhancer is glycerolmonostearate.
 8. The method of claim 3, wherein the first portioncomprises apomorphine particles having an effective particle size offrom 1 μm to 10 μm.
 9. The method of claim 3, wherein the film comprisesa polysaccharide.
 10. The method of claim 3, wherein the film comprisesfrom 2 to 40 mg of an acid addition salt of apomorphine.
 11. The methodof claim 10, wherein the film comprises from 12 to 30 mg of an acidaddition salt of apomorphine.
 12. The method of claim 10, wherein thefilm comprises 12±3 mg of an acid addition salt of apomorphine.
 13. Themethod of claim 10, wherein the film comprises 22±4 mg of an acidaddition salt of apomorphine.
 14. The method of claim 10, wherein thefilm comprises 30±5 mg of an acid addition salt of apomorphine.
 15. Themethod of claim 10, wherein the film comprises 35±5 mg of an acidaddition salt of apomorphine.
 16. The method of claim 3, wherein the pHneutralizing agent is an organic base.
 17. The method of claim 3,wherein following sublingual administration the film produces an averagecirculating apomorphine plasma concentration of at least 3 ng/mL within20 minutes.
 18. The method of claim 3, wherein the film comprises amucoadhesive polymer.